Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1992-08-14
1993-11-30
Cintins, Marianne M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
552576, 552577, 552597, 552599, 552600, 552607, 552625, 552641, C07J 500, C07J 700
Patent
active
052667120
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the field of pharmacotechnology and more particularly it relates to a process for obtaining active ingredients for pharmaceutical use having a determined size of crystals, by means of a crystallization method.
It is in fact known that the size of crystals of a pharmaceutical active ingredient plays an important role when dry or fluid pharmaceutical formulation are realized, to insure a reproducible manufacture of the formulation and hence a constant resorption.
The fact has been frequently cited in the litterature that the variations in the kinetics of dissolution are due either to alterations in the crystalline structure or of the surface properties, of the crystals, or to modifications of the extent of the surface of contact put in action (G. GILLARD Labo. Pharm. Probl. and Techn. 309 (1981) 359-369).
To improve the kinetics of dissolution of the active ingredients of drugs showing a limited solubility, a decrease of the size of the particles are often employed.
This problem is usually solved by the use of a mechanical proceeding such as grinding or micronizing (pounded by jet of air).
A study conducted on various progestatives by Muttenrauch and Cowork (STP Pharma 5(10) 1989, 642-646) has shown that the role played by the size of the crystals on the rate of dissolution was closely linked to the solubility of the organic substances.
It has been often disclosed on a large number of molecules of therapeutic use, that the size of particles and the physico-chemical properties of the active-ingredients resulting from these treatments determine the bioavailability of the pharmaceutical formulation containing them through modifications of the rates and speed of dissolution (cf. FDA paper guidelines, Manuf Control Form ANDA'S (1985). However these methods of pounding are not appropriate to pulverize all active ingredients, some of which have low melting points and become pasty or elastic. Other active ingredients because of their physical properties cannot be micronized (80% <10 .mu.m) and this despite several passages in the pounder. It has been described, namely by Nakagawa and cowork (Chem. Pharm. Bull. 30 (1982) 242) that the specific surface and the crystallinity have a great influence on the chemical stability at the solid state, of the pulverized compound.
The rate of dissolution is also dependant up on the cristallinity of the compound B. A. Hendricken disclosed it in Int. J. of Pharm. 60 243-252 (1990). Other investigators have studied the effects of mechanical treatments, such as grinding, on the physico-chemical properties of various active ingredients contained in the composition of a pharmaceutical formulation for therapeutic purpose. These workers noticed that the active ingredients show some alterations in the physico-chemical properties due to these treatments.
Among them it may be cited: analysis of the temperature of decomposition (for some active ingredients it has been noted drops in the melting points of 10.degree. to 15.degree. C.) manufacture of a mixture of powders. It has more precisely described in the previously-cited Gillard's work that the morphometric, electrical and rheological properties are very significant for the realization of a homogeneous mixture and namely these having a good flowing capacity.
All these changes in the physico-chemical characteristics on various active ingredients have been very precisely described by M. OTSUKA and N. KANENIWA in International J. of Pharmaceutics 62 (1990) 65-73 and in the references cited in this article. Moreover it cannot be forgot ten the influence of the decrease in the size of the particles produced by grinding on the hardness of tablets obtained from these compounds (cf. Y. SAGAWA J. Powder Technol. Jap. 20 (1983) 737-743).
This is why the experimental results from Tawashi (STP Pharma. 6(5) (1990) 299-302) supplied with an illustration of the relation-ship which exists between decrease in the size of the particles and morphological aspects of thus resulting fragments. The result of the mechanism of reducti
REFERENCES:
patent: 2096744 (1937-10-01), Hildebrandt et al.
patent: 2897216 (1959-07-01), Oliveto et al.
patent: 3007923 (1961-11-01), Muller et al.
patent: 3053865 (1962-09-01), Taub et al.
Cintins Marianne M.
Kestler Kimberly J.
Laboratoire Theramex S.A.
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